The overall goal of this project is to understand the mechanisms by which general anesthetics suppress consciousness and allow its return during emergence. Our general hypothesis is that anesthetics remove consciousness by disrupting functional integration across cortical neuronal networks. The proposed project builds upon our one-and-a-half decade-long investigation into the systems neuroscience mechanisms of anesthesia. In our prior work, we investigated the effect of volatile anesthetics on the power and coherence of gamma oscillations, and on their preferential role in corticocortical feedback vs. feedforward signaling as a neuronal correlate of unconsciousness. Subsequently, we focused on how the dynamics of spiking activity of cortical neurons and the complexity of their interactions were modulated by anesthetics. Here, using optogenetic and electrical microstimulation techniques, we extend this work to examine how cortical top- down, subcortical bottom-up and local state modulations alter cortical neuronal interactions associated with loss and return of consciousness. We will examine spontaneous ongoing activity and sensory stimulus-related neuronal interactions across visual and association cortex and will directly interrogate functional circuits using selective microstimulation for the first time. We will test the hypothesis that the complexity of spontaneous and stimulus-driven neuronal interactions will undergo a distinct transition associated with loss and recovery of consciousness as a function brain state modified by anesthetic dose, top-down and bottom-up modulation, and general cortical excitability. We will study the concentration-dependent effect of four representative anesthetic agents with different pharmacological profiles: desflurane, propofol, dexmedetomidine, and ketamine to find a common, agent-invariant neuronal correlate of unconsciousness. State changes at select anesthetic concentrations will be elicited by cortical or subcortical stimulation, neuronal silencing, and subnoxious somatosensory arousal. Parallel spike trains and local field potentials will be recorded from visual and adjacent association cortices using chronically implanted multielectrode arrays in unrestrained rats. Spontaneous and visual stimulus-related excitatory and inhibitory monosynaptic connectivity, neuronal interaction complexity, and microstimulation-induced effective connectivity within and between each cortical region will be derived. These experiments will provide essential new information about the role of cortical neuronal interactions in information integration as a function of conscious state and help uncover the degree to which both globally and locally driven neuronal activity is altered by brain states. The proposed work will advance our understanding of the neural mechanism of anesthesia and the neurobiological basis of consciousness at an integrative level. Our findings will augment the basic scientific knowledge necessary for the future development of novel electrophysiological monitoring of the state of consciousness and for the development of new approaches to manipulate the state consciousness for general anesthesia.

Public Health Relevance

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Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM056398-18
Application #
9309338
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1997-08-01
Project End
2021-02-28
Budget Start
2017-04-01
Budget End
2018-02-28
Support Year
18
Fiscal Year
2017
Total Cost
$319,024
Indirect Cost
$106,524
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Mashour, George A; Hudetz, Anthony G (2018) Neural Correlates of Unconsciousness in Large-Scale Brain Networks. Trends Neurosci 41:150-160
Pal, Dinesh; Silverstein, Brian H; Sharba, Lana et al. (2017) Propofol, Sevoflurane, and Ketamine Induce a Reversible Increase in Delta-Gamma and Theta-Gamma Phase-Amplitude Coupling in Frontal Cortex of Rat. Front Syst Neurosci 11:41
Mashour, George A; Hudetz, Anthony G (2017) Bottom-Up and Top-Down Mechanisms of General Anesthetics Modulate Different Dimensions of Consciousness. Front Neural Circuits 11:44
Todorov, Mihail I; Kékesi, Katalin A; Borhegyi, Zsolt et al. (2016) Retino-cortical stimulus frequency-dependent gamma coupling: evidence and functional implications of oscillatory potentials. Physiol Rep 4:
Hudetz, Anthony G; Mashour, George A (2016) Disconnecting Consciousness: Is There a Common Anesthetic End Point? Anesth Analg 123:1228-1240
Hudetz, Anthony G; Vizuete, Jeannette A; Pillay, Siveshigan et al. (2016) Repertoire of mesoscopic cortical activity is not reduced during anesthesia. Neuroscience 339:402-417
Hudetz, Anthony G; Liu, Xiping; Pillay, Siveshigan et al. (2016) Propofol anesthesia reduces Lempel-Ziv complexity of spontaneous brain activity in rats. Neurosci Lett 628:132-5
Hudetz, Anthony G; Vizuete, Jeannette A; Pillay, Siveshigan et al. (2015) Critical Changes in Cortical Neuronal Interactions in Anesthetized and Awake Rats. Anesthesiology 123:171-80
Hudetz, Anthony G; Liu, Xiping; Pillay, Siveshigan (2015) Dynamic repertoire of intrinsic brain states is reduced in propofol-induced unconsciousness. Brain Connect 5:10-22
Pillay, Siveshigan; Liu, Xiping; Baracskay, Péter et al. (2014) Brainstem stimulation increases functional connectivity of basal forebrain-paralimbic network in isoflurane-anesthetized rats. Brain Connect 4:523-34

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